Role of NO and S-nitrosylation in the Expression of Endothelial Adhesion Proteins That Regulate Leukocyte and Tumor Cell Adhesion

Aguilar, Gaynor; Köning, Tania; Ehrenfeld, Pamela; Sánchez, Fabiola A.

doi:10.3389/fphys.2020.595526

Cited by 16 publications

(7 citation statements)

References 153 publications

(226 reference statements)

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“…Our results showing NO as a signal that promotes cell adhesion to the endothelium are in strong contrast to studies showing an inhibitory role of NO in this process [ 16 , 24 , 38 , 73 ]. Besides the differences in the cell and animal models used, we propose that these discrepancies can be explained by the fact that the physiological effects of NO strictly depend on its concentration, duration of exposure, location, and activity of NOS isoforms [ 2 , 3 ]. In non-stimulated cells, basal NO production could maintain an anti-adhesive phenotype [ 23 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

Koning,

Cordova,

Aguilar

et al. 2023

Biol Res

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Background Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown. Results We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases. Conclusions S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

Koning,

Cordova,

Aguilar

et al. 2023

Biol Res

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“…Another PTM that forms part of this cluster is S-nitrosylation of the active site cysteine, which has been has been reported to reduce the activity of the UBE2D enzymes, with downstream effects on CHIP/STUB1 and on the targeting of misfolded proteins by endoplasmic reticulum-associated protein degradation (ERAD) ( Valek et al, 2019 ; Fujikawa et al, 2020 ). S-nitrosylation has been implicated in pro- and anti-inflammatory effects, promotion of apoptosis and a wide range of other biological processes ( Foster et al, 2003 ; Hara et al, 2005 ; Aguilar et al, 2020 ).…”

Section: The Ube2d Proteins Have Multiple Roles In Vertebrate Signall...mentioning

confidence: 99%

The UBE2D ubiquitin conjugating enzymes: Potential regulatory hubs in development, disease and evolution

Román-Trufero

Dillon

2022

Front. Cell Dev. Biol.

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Ubiquitination of cellular proteins plays critical roles in key signalling pathways and in the regulation of protein turnover in eukaryotic cells. E2 ubiquitin conjugating enzymes function as essential intermediates in ubiquitination reactions by acting as ubiquitin donors for the E3 ubiquitin ligase enzymes that confer substrate specificity. The members of the UBE2D family of E2 enzymes are involved in regulating signalling cascades through ubiquitination of target proteins that include receptor tyrosine kinases (RTKs) and components of the Hedgehog, TGFβ and NFκB pathways. UBE2D enzymes also function in transcriptional control by acting as donors for ubiquitination of histone tails by the Polycomb protein Ring1B and the DNA methylation regulator UHRF1 as well as having roles in DNA repair and regulation of the level of the tumour suppressor p53. Here we review the functional roles and mechanisms of regulation of the UBE2D proteins including recent evidence that regulation of the level of UBE2D3 is critical for controlling ubiquitination of specific targets during development. Cellular levels of UBE2D3 have been shown to be regulated by phosphorylation, which affects folding of the protein, reducing its stability. Specific variations in the otherwise highly conserved UBE2D3 protein sequence in amniotes and in a subgroup of teleost fishes, the Acanthomorpha, suggest that the enzyme has had important roles during vertebrate evolution.

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“…In addition, NO is also involved in leukocyte chemotaxis and infiltration. High NO concentrations after iNOS stimulation inhibit protein adhesion expression on endothelial cells due to S-nitrosylation of p50 and p65 in NF-κB and IKKβ ( Aguilar et al, 2020 ). Furthermore, NO also acts via cGMP dependent pathway.…”

Section: Role Of Nitric Oxide On the Regulation Of Immune Responsesmentioning

confidence: 99%

Nitric Oxide System and Bronchial Epithelium: More Than a Barrier

et al. 2021

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Airway epithelium forms a physical barrier that protects the lung from the entrance of inhaled allergens, irritants, or microorganisms. This epithelial structure is maintained by tight junctions, adherens junctions and desmosomes that prevent the diffusion of soluble mediators or proteins between apical and basolateral cell surfaces. This apical junctional complex also participates in several signaling pathways involved in gene expression, cell proliferation and cell differentiation. In addition, the airway epithelium can produce chemokines and cytokines that trigger the activation of the immune response. Disruption of this complex by some inflammatory, profibrotic, and carcinogens agents can provoke epithelial barrier dysfunction that not only contributes to an increase of viral and bacterial infection, but also alters the normal function of epithelial cells provoking several lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or lung cancer, among others. While nitric oxide (NO) molecular pathway has been linked with endothelial function, less is known about the role of the NO system on the bronchial epithelium and airway epithelial cells function in physiological and different pathologic scenarios. Several data indicate that the fraction of exhaled nitric oxide (FENO) is altered in lung diseases such as asthma, COPD, lung fibrosis, and cancer among others, and that reactive oxygen species mediate uncoupling NO to promote the increase of peroxynitrite levels, thus inducing bronchial epithelial barrier dysfunction. Furthermore, iNOS and the intracellular pathway sGC-cGMP-PKG are dysregulated in bronchial epithelial cells from patients with lung inflammation, fibrosis, and malignancies which represents an attractive drug molecular target. In this review we describe in detail current knowledge of the effect of NOS-NO-GC-cGMP-PKG pathway activation and disruption in bronchial epithelial cells barrier integrity and its contribution in different lung diseases, focusing on bronchial epithelial cell permeability, inflammation, transformation, migration, apoptosis/necrosis, and proliferation, as well as the specific NO molecular pathways involved.

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Role of NO and S-nitrosylation in the Expression of Endothelial Adhesion Proteins That Regulate Leukocyte and Tumor Cell Adhesion

Cited by 16 publications

References 153 publications

S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

The UBE2D ubiquitin conjugating enzymes: Potential regulatory hubs in development, disease and evolution

Nitric Oxide System and Bronchial Epithelium: More Than a Barrier

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